ECTRIMS: Early Alemtuzumab Still Works at Five Years

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Explain to interested patients that this study showed alemtuzumab was superior to subcutaneous interferon beta-1a in warding off disability in multiple sclerosis.

Note that the main adverse effect of alemtuzumab was a risk of autoimmune thyoid disease in 30% of patients.

GOTHENBURG, Sweden -- Two annual treatments with alemtuzumab prevent progression of disability in multiple sclerosis patients for up to five years, according to a study presented here.

"The news is that at five years, the data are as good as they were at three years," said lead investigator Alasdair Coles, PhD, FRCP, from the University of Cambridge, U.K., speaking here at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting.

"That's the up side. There is a down side," he said. Treatment comes with a risk of autoimmune thyroid disease in 30% of patients, which Coles characterized as a manageable risk, as well as rarer but more serious autoimmune disorders.

In the three-year randomized trial, published in 2008, two annual treatments with alemtuzumab reduced the risk of sustained accumulation of disability by 71%, superior to the 43% reduction achieved by the active comparator in the trial, daily subcutaneous interferon beta-1a (Rebif).

The five-year data included the 67% of alemtuzumab patients and 41% of interferon patients available for follow-up. No additional alemtuzumab treatments were given, while interferon patients continued daily treatment. A proportion of each group switched to other disease-modifying therapy in the follow-up period.

At five years, in those patients still available for follow-up, alemtuzumab remained superior to interferon in the proportion of patients remaining free of disability, as well as in the relapse rate and the mean change from baseline disability score as measured by the Expanded Disability Status Scale (EDSS).

The proportion of patients free of sustained accumulation of disability (no increase of EDSS sustained for at least six months) was 87% for alemtuzumab and 62% for interferon. Among those receiving no alternative disease-modifying treatments, the figures were 87% and 69%, respectively.

The mean change from baseline in EDSS improved by 0.30 points in alemtuzumab-treated patients; there was no improvement in those receiving interferon, in fact there was a decline from baseline of 0.46 points. "The disability of patients treated with alemtuzumab improved. This is not usually seen in MS trials," Coles said. Patients enrolled in the original trial were very early in their disease, with minimal disability.

"The main adverse effect is a risk of autoimmune thyroid disease, in 30% of patients," he said, adding that "we don't have a complete explanation [for it]." The drug works by profoundly depleting lymphocytes, with a reconstitution over the course of two or more years.

The greatest risk is for people with a specific genotype, Coles said, allowing some risk stratification with a genetic test before treatment. Patients at higher risk who opted for treatment might be put on an intensive monitoring program, he suggested. Patients who have developed uncontrolled disease have received thyroid ablation and subsequent thyroid hormone pills.

Rarer but more severe autoimmune disorders seen with treatment included immune thrombocytopenic purpura (ITP) in six patients and leading to one death, and one case of Goodpasture's disease (anti-glomerular basement membrane disease), treated successfully.

"We don't pretend alemtuzumab is risk-free, but the risks are to some extent predictable and treatable," Coles said.

Should the drug be marketed, he suggested that treatment would include a "package deal" of long-term surveillance.

Richard Rudick, MD, professor of medicine at the Cleveland Clinic in Ohio, who was not involved in the study, was cautiously optimistic about the new results. "The issue we always run into [with such long-term follow-up] is that the people at the end are doing well, but there are many patients lost to follow-up. Having said that, long-term follow-up is really important."

The risk of major autoimmune disease "will presumably be the principal issue," he said. "I think it's too early to say whether we are going to see opportunistic infections, or cancers for that matter. We will need to see larger numbers of patients tested over longer periods of time."

Rudick added that "the principal concern about alemtuzumab will be how it stacks up against natalizumab. Natalizumab is very effective, but has the complication of progressive multifocal leukoencephalopathy. But the advantage of natalizumab is that when you stop the drug, you clear it quickly, and in a short period of time you reverse the effects. Once you give alemtuzumab, you have pretty profound leukopenia for a year, and it's not clear what you can do about it."

Coles has received funding from Genzyme Corporation, the manufacturer of alemtuzumab.

Rudick has received compensation from BiogenIdec, Wyeth, Genzyme-Bayer, Bayhill Pharmaceuticals, Teva, and Novartis.

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